After getting in some trouble as a youth, he enrolled at the National Black Theatre in New York City. He later got a job at a pharmaceutical company. Inspired by Janet Jackson's Rhythm Nation 1814, he left school and quit his job, against the wishes of his family, to pursue a career as a dancer. During a year in which he was intermittently homeless, Williams visited record labels and dance studios looking for work. He got a job as a background dancer on a music tour for Kym Sims' dance anthem Too Blind To See It, which led to more work appearing as a dancer in videos and on tours, such as with George Michael, Madonna, as well as some modeling work. He also choreographed Crystal Waters' 1994 single 100% Pure Love.[8][9]

He was given one of his first acting roles after being discovered by Tupac Shakur and was cast as High Top, the brother and henchman to Shakur's drug kingpin Tank, in the 1996 film Bullet.[10]

Williams is well known for his large facial scar, which he received during a bar fight on Jamaica Avenue on his 25th birthday in which he was slashed with a razor blade.[11] The scar led to his being offered roles as a thug in music videos.[11] He eventually embraced the scar, citing Seal's scarred face as an inspiration. His scar became his signature and earned him photo shoots with noted photographers like David LaChapelle.

Williams at Harvard University for a panel discussion on The Wire, November 8, 2010

Williams is known for his portrayal of Omar Little in The Wire, which began filming in 2002. The character was based on Donnie Andrews, as well as other crime figures in Baltimore.[13] Williams received the part after only a single audition.[14] He was initially told that the character was slated to appear in just seven episodes of the first season and feared that the character would be killed before the end of the season.[14] However, creator David Simon stated that they always planned to keep the character as part of the continuing ensemble should the show be renewed beyond the first season.

For his portrayal of Omar, Williams was named by USA Today as one of ten reasons they still love television. The character was praised for his uniqueness in the stale landscape of TV crime dramas and for the wit and humor that Williams brings to the portrayal.[1] Omar has been named as one of the first season's richest characters, a Robin Hood of Baltimore's west side projects. The Baltimore City Paper named the character one of their top ten reasons not to cancel the show and called him "arguably the show’s single greatest achievement".[3] In 2007 he was nominated for an NAACP Image Award for Outstanding Actor in a Drama Series for his role as Omar.[15]

Williams pursued the role because he was intrigued by the character's contradictory nature.[14] He felt the character's popularity stemmed from his honesty, lack of materialism, individuality and his adherence to his strict code.[14] He feels that the role has been a breakthrough in terms of bringing attention to him and getting further roles.[16] Williams has received both positive and negative reactions to the character's homosexuality and feels that he is successful in challenging attitudes and provoking discussion with the role.[16] During the previous year, before the third season, he discovered Felicia Pearson (Snoop) in a Baltimore bar.

In 2008, then-U.S. Senator Barack Obama cited The Wire as his favorite television show, and called Omar Little his favorite character. About Omar, Obama said, "That’s not an endorsement. He's not my favorite person, but he's a fascinating character... he's the toughest, baddest guy on the show."[17]

Williams suffered from an identity crisis during his portrayal of Omar Little, going by his character's name, and developed a habit of smoking cannabis and an addiction to cocaine in 2004.[18][19]

Williams makes a brief appearance as the shooter at the beginning of the music video for Young Jeezy's "Bury Me a G".

He appeared in The Kill Point as recurring guest star Q, a police sniper alongside The Wire co-stars J.D. Williams, Michael Hyatt and Leo Fitzpatrick. He auditioned for the starring role of Mr. Cat but was forced to take a smaller role due to scheduling conflicts; the part of Mr. Cat went to J.D. Williams instead.[20] Williams played a Boston area detective named Devin Amronklin in the 2007 film Gone, Baby, Gone. The film is based on a novel by Dennis Lehane, who has written for The Wire, and was adapted and directed by Ben Affleck. Amronklin is a recurring character in Lehane's Kenzie-Genarro series of books. Williams says that he enjoyed working with Affleck and characterized him as a passionate and hands-on director.[16] The film also featured his co-star from The Wire, Amy Ryan.

Williams also starred in the film A Day in the Life, which was directed, produced and stars rapper Sticky Fingaz. The entire film is a musical with every line being delivered in rap verse. Williams starred in HBO's Boardwalk Empire for its 5 seasons (2010-2014). He appeared as Albert "Chalky" White, the leader of 1920s Atlantic City's black community.

On July 23, 2011, Community creator Dan Harmon revealed that Williams would star in "at least three episodes" of the sitcom's third season.[23] He plays the role of Biology Professor Marshall Kane at Greendale Community College. In November 2011, it was announced that Quentin Tarantino has written a new character into the script of his new film Django Unchained.[24] Williams, who had previously confirmed that he was actually in talks with Tarantino to take on the titular role of Django,[25] was to portray a minor character in the film, but scheduling conflicts with Boardwalk Empire prevented him from doing so.

On May 16, 2012, Williams announced that he is an executive producer of the independent film Snow On Tha Bluff, Williams' first film under his company, Freedome Productions. On Power 105.1fm's The Breakfast Club, Williams revealed the June 19th release date for Snow on tha Bluff, describing the movie as "real graphic": "everything that is wrong with the 'hood is in this movie".[26]Williams also shared on 105.1The Breakfast Club that he is starring in an African American western "They Die By Dawn" with his co-star Snoop from the HBO series "The Wire". Williams also revealed that he is starring in the lead role as Ol'Dirty Bastard from the Wu-Tang Clan in the movie Dirty Whiteboy in 2014. Which is based on the relationship ODB had with his manager during the last 2 years of his life. Williams mentioned the piece was special to Ol'Dirty Bastard (ODB) because he grew up listening to him and to Wu-Tang and he is also a Brooklyn native.[27]